The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial.

Background: There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE).

Objective: To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE.

Design: Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002.

Shedding of endothelial protein C receptor contributes to vasculopathy and renal injury in lupus: in vivo and in vitro evidence.

Background: Candidate biomarkers for vasculopathy in systemic lupus erythematosus (SLE) include circulating endothelial cells and the recently identified endothelial protein C receptor (EPCR) which, when shed, promotes a thrombotic diathesis. This study sought correlation between plasma levels of soluble EPCR and disease manifestation/severity, with a focus on lupus nephritis.

Methods: In 81 SLE patients (evaluated cross-sectionally and longitudinally) and 59 healthy controls, levels of soluble EPCR and soluble E-selectin were assessed by sandwich enzyme-linked immunosorbent assay (ELISA), circulating endothelial cells isolated by immunomagnetic separation, and EPCR gene polymorphisms determined.

Neonatal lupus: basic research and clinical perspectives.

Neonatal lupus, although quite rare, carries a significant mortality and morbidity when the fetal heart is the targeted organ. Anti-SSA/Ro-SSB/La antibodies are present in more than 85% of mothers whose fetuses are identified with congenital heart block (CHB) in a structurally normal heart, but the risk for a woman who has the candidate antibodies to have a child who has CHB is approximately 2%. Although the precise pathogenic mechanism of injury remains unknown, it is clear that the antibodies alone are insufficient to cause disease, and fetal factors are likely contributory.

Circulating endothelial cells. Biomarker of vascular disease.

Recent research has recognised new populations of non-hematopoietic cells in the blood. One of these, circulating endothelial cells (CECs), often defined by the expression of membrane glycoprotein CD146, are rarely found in the blood in health, but raised numbers are present in a wide variety of human conditions, including inflammatory, immune, infectious, neoplastic and cardiovascular disease, and seem likely to be evidence of profound vascular insult. An additional population are endothelial progenitor cells, defined by the co-expression of endothelial and immaturity cell surface molecules and also by the ability to form colonies in vitro.

Autoantibody-associated congenital heart block: TGFbeta and the road to scar.

Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus (NL), often referred to as a model of passively acquired autoimmunity. The signature histologic lesion of autoimmune congenital heart block (CHB) is fibrosis of the conducting tissue and, in some cases, the surrounding myocardium. It is astounding how rapid, and in most cases, irreversible, the fibrotic response to injury is.

Challenges in bringing the bench to bedside in drug development for SLE.

It is now widely accepted that the current standard of care for systemic lupus erythematosus (SLE) patients is inadequate. There has not been a new medication approved for this disease in thirty years. Attempts to develop and test new drugs have been ongoing since the mid-1990s, but have encountered formidable obstacles.

Anti-52 kDa Ro, anti-60 kDa Ro, and anti-La antibody profiles in neonatal lupus.

Objective: Studies suggest that anti-52 kDa Ro antibodies are more sensitive and specific than anti-60 kDa Ro antibodies for neonatal lupus. However, these studies mainly used immunoblot or ELISA using recombinant protein, which have poor sensitivity for anti-60 kDa Ro antibodies. In addition, the control patients were not disease matched.

Neonatal lupus syndromes.

The neonatal lupus syndromes (NLS), while quite rare, carry significant mortality and morbidity in cases of cardiac manifestations. Although anti-SSA/Ro-SSB/La antibodies are detected in > 85% of mothers whose fetuses are identified with congenital heart block (CHB) in a structurally normal heart, when clinicians applied this testing to their pregnant patients, the risk for a woman with the candidate antibodies to have a child with CHB was at or below 1 in 50. While the precise pathogenic mechanism of antibody-mediated injury remains unknown, it is clear that the antibodies alone are insufficient to cause disease and fetal factors are likely contributory.

Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus.

Objective: To determine whether prasterone administration results in improvement or stabilization of systemic lupus erythematosus (SLE) disease activity and its symptoms.

Methods: Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for up to 12 months in this randomized, double-blind investigation conducted at 27 centers. Standard SLE treatments included prednisone (/=6 weeks prior to enrollment and remain unchanged during protocol treatment.

Autoimmune-associated congenital heart block: dissecting the cascade from immunologic insult to relentless fibrosis.

Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus, often described as a model of passively acquired autoimmunity. The signature histologic lesion of autoimmune congenital heart block (CHB) is fibrosis of the conducting tissue and, in some cases, the surrounding myocardium. Although anti-SSA/Ro-SSB/La antibodies are detected in > 85% of mothers whose fetuses are identified with conduction abnormalities in a structurally normal heart, the risk for a woman with the candidate antibodies to have a child with CHB is 2%.

Genetic association of cutaneous neonatal lupus with HLA class II and tumor necrosis factor alpha: implications for pathogenesis.

Objective: Cutaneous neonatal lupus resembles subacute cutaneous lupus erythematosus (SCLE), and photosensitivity is a common symptom. Tumor necrosis factor alpha (TNFalpha) release by ultraviolet light-exposed keratinocytes may be exaggerated in SCLE patients who have the haplotype TNFalpha -308A;DRB1*03. Accordingly, this study was undertaken to seek genetic and histologic evidence for a role of TNFalpha in the pathogenesis of cutaneous neonatal lupus.

More to death than dying: apoptosis in the pathogenesis of SSA/Ro-SSB/La-associated congenital heart block.

The mechanism by which maternal anti-SSA/Ro-SSB/La antibodies initiate and perpetuate inflammation and eventuate in scarring of the atrioventricular node (the signature lesion of congenital heart block) is not yet defined. In vitro and in vivo studies suggest that one pathologic cascade that leads to scarring may be initiated by way of apoptosis which results in translocation of SSA/Ro-SSB/La antigens and subsequent surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages,which secrete factors that modulate fibroblasts into myofibroblasts,a scarring phenotype.

Immunohistologic evidence supports apoptosis, IgG deposition, and novel macrophage/fibroblast crosstalk in the pathologic cascade leading to congenital heart block.

Objective: To assess in vivo the pathologic cascade leading to fibrosis in congenital heart block (CHB). In vitro studies suggest that CHB is initiated via apoptosis, resulting in translocation of SSA/Ro and SSB/La antigens and surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors inducing fibrosis.

From antibody insult to fibrosis in neonatal lupus - the heart of the matter.

Few diseases exemplify the integration of research from bench to bedside as well as neonatal lupus, often referred to as a model of passively acquired autoimmunity. In essence, this disease encompasses two patients, both the mother and her child. The signature histologic lesion of autoimmune-associated congenital heart block is fibrosis of the conducting tissue, and in some cases the surrounding myocardium.

The fetal Doppler mechanical PR interval: a validation study.

Objective: To evaluate the accuracy of pulsed Doppler-derived fetal PR interval measurements obtained by physicians participating in a multicenter prospective fetal echocardiographic study.

Methods: Echocardiograms on healthy fetuses were performed and evaluated by 15 pediatric cardiologists/perinatologists across the United States who are participating in a larger clinical trial involving fetuses at risk for autoantibody-associated congenital heart block. Prior to enrolling women in the main trial, each physician was provided with a teaching tape to demonstrate how the pulsed Doppler-derived PR interval is measured.

Myocardial-tissue-specific phenotype of maternal microchimerism in neonatal lupus congenital heart block.

Background: During pregnancy, maternal cells pass into the fetus, where they can persist for many years after birth. We investigated the presence of maternal cells in neonatal lupus syndrome (NLS), an autoimmune disease that develops in utero. The most serious complication of NLS is inflammation of the atrioventricular node leading to congenital heart block (CHB).

Autoantibody-associated congenital heart block: the clinical perspective.

Congenital heart block (CHB) can occur in association with structural heart disease, such as atrioventricular septal defects, left atrial isomerism, and abnormalities of the great arteries, with tumors, such as mesotheliomas, or as an isolated defect. In 1928, Aylward reported the occurrence of CHB in two children whose mother "suffered from Mikulicz's disease." This curious clinical observation was further solidified by the 1970s, with reports of CHB in children whose mothers had autoimmune diseases and that the maternal sera contained antibodies to Ro ribonucleoproteins.

Neonatal lupus syndromes.

The neonatal lupus syndromes, although quite rare, provide an excellent opportunity to examine disease from bench to bedside. During the past year numerous publications have reported basic and clinical research. Although anti-SSA/Ro-SSB/La antibodies are detected in more than 85% of mothers whose fetuses are identified with conduction abnormalities in a structurally normal heart, when clinicians applied this testing to their pregnant patients, the risk for a woman with the candidate antibodies to have a child with congenital heart block was at or below one in 50.

Cytokine polymorphisms and histologic expression in autopsy studies: contribution of TNF-alpha and TGF-beta 1 to the pathogenesis of autoimmune-associated congenital heart block.

Although Abs to SSA/Ro-SSB/La are necessary for the development of congenital heart block (CHB), the low frequency suggests that fetal factors are contributory. Because CHB involves a cascade from inflammation to scarring, polymorphisms of the TNF-alpha promoter region and codons 10 and 25 of the TGF-beta gene were evaluated in 88 children (40 CHB, 17 rash, 31 unaffected siblings) and 74 mothers from the Research Registry for Neonatal Lupus (NL). Cytokine expression was assessed in autopsy material from two fetuses with CHB.

Clearance of apoptotic cells: TGF-beta in the balance between inflammation and fibrosis.

Transforming growth factor-beta (TGF-beta) has been considered an anti-inflammatory cytokine responsible for the bland removal of apoptotic cells. What is less established is the extent of secretion of this cytokine during the clearance of opsonized apoptotic cells via Fcgamma-mediated uptake. To date both decreased (favoring predominance of inflammation) and increased (favoring resolution of inflammation but potentially pro-fibrotic) responses have been demonstrated.